PMID- 36518267 OWN - NLM STAT- MEDLINE DCOM- 20230120 LR - 20230120 IS - 2167-8359 (Print) IS - 2167-8359 (Electronic) IS - 2167-8359 (Linking) VI - 10 DP - 2022 TI - Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach. PG - e14132 LID - 10.7717/peerj.14132 [doi] LID - e14132 AB - BACKGROUND: Primary congenital glaucoma (PCG) is the most common subtype of glaucoma caused by defects in the cytochrome P450 1B1 (CYP1B1) gene. It is developing among infants in more than 80% of cases who exhibit impairments in the anterior chamber angle and the trabecular meshwork. Thus, a comprehensive in silico approach was performed to evaluate the effect of high-risk deleterious missense variations in the CYP1B1 gene. MATERIAL AND METHODS: All the information for CYP1B1 missense variants was retrieved from the dbSNP database. Seven different tools, namely: SIFT, PolyPhen-2, PROVEAN, SNAP2, PANTHER, PhD-SNP, and Predict-SNP, were used for functional annotation, and two packages, which were I-Mutant 2.0 and MUpro, were used to predict the effect of the variants on protein stability. A phylogenetic conservation analysis using deleterious variants was performed by the ConSurf server. The 3D structures of the wild-type and mutants were generated using the I-TASSER tool, and a 50 ns molecular dynamic simulation (MDS) was executed using the GROMACS webserver to determine the stability of mutants compared to the native protein. Co-expression, protein-protein interaction (PPI), gene ontology (GO), and pathway analyses were additionally performed for the CYP1B1 in-depth study. RESULTS: All the retrieved data from the dbSNP database was subjected to functional, structural, and phylogenetic analysis. From the conducted analyses, a total of 19 high-risk variants (P52L, G61E, G90R, P118L, E173K, D291G, Y349D, G365W, G365R, R368H, R368C, D374N, N423Y, D430E, P442A, R444Q, F445L, R469W, and C470Y) were screened out that were considered to be deleterious to the CYP1B1 gene. The phylogenetic analysis revealed that the majority of the variants occurred in highly conserved regions. The MD simulation analysis exhibited that all mutants' average root mean square deviation (RMSD) values were higher compared to the wild-type protein, which could potentially cause CYP1B1 protein dysfunction, leading to the severity of the disease. Moreover, it has been discovered that CYP1A1, VCAN, HSD17B1, HSD17B2, and AKR1C3 are highly co-expressed and interact with CYP1B1. Besides, the CYP1B1 protein is primarily involved in the metabolism of xenobiotics, chemical carcinogenesis, the retinal metabolic process, and steroid hormone biosynthesis pathways, demonstrating its multifaceted and important roles. DISCUSSION: This is the first comprehensive study that adds essential information to the ongoing efforts to understand the crucial role of genetic signatures in the development of PCG and will be useful for more targeted gene-disease association studies. CI - (c)2022 Shahid et al. FAU - Shahid, Muhammad AU - Shahid M AD - Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. FAU - Azfaralariff, Ahmad AU - Azfaralariff A AD - Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. FAU - Tufail, Muhammad AU - Tufail M AD - Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan. FAU - Hussain Khan, Nazeer AU - Hussain Khan N AD - School of Life Sciences, Henan University, Kaifeng, Henan, China. FAU - Abdulkareem Najm, Ahmed AU - Abdulkareem Najm A AD - Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. FAU - Firasat, Sabika AU - Firasat S AD - Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan. FAU - Zubair, Muhammad AU - Zubair M AD - Department of Wildlife and Ecology, University of Veterinary and Animal Sciences, Pattoki Campus, Pattoki, Punjab, Pakistan. FAU - Fazry, Shazrul AU - Fazry S AD - Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. AD - Tasik Chini Research Center, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia. FAU - Law, Douglas AU - Law D AD - Faculty of Health and Life Sciences, Inti International University, Persiaran Perdana BBN Putra Nilai, Nilai, Negeri Sembilan, Malaysia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221130 PL - United States TA - PeerJ JT - PeerJ JID - 101603425 RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.14.1 (CYP1B1 protein, human) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1B1) MH - Infant MH - Humans MH - Mutation MH - Phylogeny MH - Pedigree MH - *Cytochrome P-450 Enzyme System/genetics MH - *Glaucoma/genetics MH - Cytochrome P-450 CYP1B1/genetics PMC - PMC9744154 OTO - NOTNLM OT - CYP1B1 OT - In silico OT - Missense variations OT - Modeling OT - Molecular dynamic simulation OT - Primary congenital glaucoma COIS- The authors declare there are no competing interests. EDAT- 2022/12/16 06:00 MHDA- 2022/12/16 06:01 PMCR- 2022/11/30 CRDT- 2022/12/15 02:18 PHST- 2022/06/23 00:00 [received] PHST- 2022/09/06 00:00 [accepted] PHST- 2022/12/15 02:18 [entrez] PHST- 2022/12/16 06:00 [pubmed] PHST- 2022/12/16 06:01 [medline] PHST- 2022/11/30 00:00 [pmc-release] AID - 14132 [pii] AID - 10.7717/peerj.14132 [doi] PST - epublish SO - PeerJ. 2022 Nov 30;10:e14132. doi: 10.7717/peerj.14132. eCollection 2022.